The field of the invention is anti-inflammatory agents.
Boron compounds are known to show a variety of different biological activities. Very often, boron compounds show enzyme inhibitory activity, and thus boron compounds can inhibit a number of enzymes alone or in a mixture with various co-inhibitors. For example, borates inhibit L-amino acid oxidase in a mixture with butanedione by interacting with the arginine residue in the active site. (Christman M F, Cardenas J M: Experientia 38 (5): 537-538 (1982)).
Similarly, borates and butanedione inhibit citrate/isocitrate-hydro-lyase, EC 4.2.1.3, again by interacting with the arginine residue from the active site. (Gawron O, Jones L: Biochem Biophys Acta 484 (2): 453-464 (1977)). Also, 2,3-butanedione or 1,2-cyclohexanedione in the presence of borates interact specifically with the guanidino group from arginine, and this fact was used for determination of arginine residues in the active site of the examined enzymes. In this way Dietl, T. and Tschesche, H . (Hoppe Seylers Z Physiol Chem: 357 (5): 657-665 (1976)) proved arginine residue is present in the active site of proteinases.
Borates (at low concentration) are also known to inhibit glyceraldehyde-3-phosphate dehydrogenase from human, pig and rabbit muscle. However, in greater concentration (above 6 mM) borates inhibit esterase and acetylphosphatase activities. (Wolny M: Eur J Biochem 80 (2): 551-556 (1977)).
An interesting biological activity of borates was noticed in the case of palytoxin induction of the histamine release from rat mast cells. In the presence of borates the activity of palytoxin was increased ten times (Chhatwal G S, Ahnert-Hilger G, Beress l, Habermann E: Int Arch Allergy Appl Immunol 68 (2): 97-100 (1982)).
Borates inhibit methylation of catechol estrogen and pyrocatechol by catechol-O-methyltransferase (Beattie J H, Weersink E: J Inorg Biochem 46 (3): 153-160 (1992)).
Several naturally occurring antibiotics contain boron as an essential structural element (such as boromycin, an anti-HIV antibiotic (Kohno J, et al: Biosci Biotechnol Biochem (Japan) 60(6), 1036-7 (1996), or tetralons, new boron-containing antibiotics from a myxobacterium, Sorangium cellulosum (Irschik H, Schummer D, Gerth K, Hofle G, Reichenbach H: J Antibiot (Tokyo) (Japan), 48 (1), 26-30 (1995)).
Borates and some of their organic complexes are experimentally used in surgery as agents which promote healing of open wounds (Humzah M D, Marshall J, Breach N M: J R Coll Surg Edinb (England) 41(4), 269-70 (1996); McCowan M, Aitken F: J Wound Care (England), 6(5), 248-249 (1997); Bliss M R: J Wound Care (England) 6(5), 248-249 (1997)).
Larvicidal effects of ingestion of boric acid and disodium octaborate tetrahydrate by cat fleas was recently described by Hinkle N C, Koehler P G, and Patterson R S in J Med Entomol (United States), July 1995,32(4), p 424-7.
Some specific organoboron compounds (such as cyanotriphenylborate) were shown to be subtype-specific blockers of glycine receptor chloride channels (Rundstrom N, Schmieden V, Betz H, Bormann J, Langosch D: Proc Natl Acad Sci USA (United States), 91(19), 8950-4 (1994)).
A very important biological behavior of certain boron compounds is their interaction with Ca-metabolism. Namely, it has been noticed (Benderdour M, Hess K, Dzondo-Gadet M, Dousset B: Biochem Biophys Res Commun 234 (1), 263-8 (1997)) that boric acid itself, acting upon a pelvic cartilage of chick embryo, induced release of proteoglycans, collagen and other proteins, but at the same time strongly decreased their intracellular synthesis. However, surprisingly enough, boric acid in the presence of a great molar excess of glucose did not decrease intracellular biosynthesis of proteins, but still induced efficiently their intensive secretion. The effect can not be ascribed to a boron toxicity, since the cell membranes were intact (observed by electronic microscopy) and the cells were secretory. It was assumed that boron interacted actively with Ca-metabolism (see, in addition to this article, Nielsen F, Muller L, Gallgher S: J Trace Elem Exp Med 3, 45-54 (1990); Nielsen F H: FASEB 5, 2661-7 (1991)). Benderdour et al postulated that boric acid or its glucose complex can inhibit serine/threonine phosphatases.
Specific biological calcium-boron interaction is also supported by a work of T. Maruyama et al (J Biochem (Tokyo), 122(3), 498-505 (1997)) who showed that 2-aminoethoxydiphenyl borate (2 APB) inhibited Ins (1,4,5) P3-induced Ca2+ release from rat cerebellar microsomal preparations. At the same time, addition of 2 APB to the extracellular environment inhibited the cytosolic Ca2+ rise in intact cells such as human platelets and neutrophiles stimulated by thrombin or leukotriene B4 (LTB4).
The present applicant has evidence showing that Boron has and anti-inflammatory action when taken as a nutritional supplement. Supplemental boron is known in many different forms. As over-the-counter supplements, for example, boron is marketed as calcium borogluconate (Now Foods, Glendale Hts., Ill.), and as boron citrate, aspartame and glycinate chelates (Twin Laboratories, Inc., Ronkonkoma, N.Y.). U.S. Pat. No. 4,849,220 to Hunt, issued Jul. 18, 1989, describes the addition of boric acid (H3BO3) to the diet of postmenopausal women, and U.S. Pat. No. 5,312,816 to Spielvogel et al. describes dietary supplementation with Lewis-acid base boron adducts. Boron has also been given as a simple salt, such as sodium borate, or sodium tertraborate decahydrate.
Unfortunately, these known forms of boron supplementation have noticeably undesirable side effects, rendering the known forms of boron supplementation somewhat undesirable as anti-inflammatory agents. First, the known forms either contain or are readily hydrolyzed in the gut to boric acid. Boric acid is reactive, and tends to accumulate in tissues other than bone or joint. Second, the amount of boron made available by known supplementation is extremely high compared with normal blood values. A typical boron supplement, for example, may make almost 3 mg of elemental boron available to the tissues within a half hour after ingestion, which is about 14 times the normal total blood boron of 213 xcexcg. (Hunt, C. D., et al., xe2x80x9cRDA Workshop: New Approaches, Endpoints and Paradigms for RDAs of Mineral Elementsxe2x80x9d, American Institute of Nutrition, 1996, pp 2441S-2451S). Third, while there is a mechanism which limits boron absorption from foods when boron intake is high, (Hunt, C. D., et al., xe2x80x9cRDA Workshop . . . xe2x80x9d, supra), that mechanism likely does not act to prevent the almost immediate availability of boron from currently known supplements. Fourth, it has been estimated that less than a quarter of the population takes vitamin/mineral supplements on a daily basis, so that the known forms of supplementation are unlikely to reach a high percentage of the population.
Thus, there is still a need to provide in forms and formulations for use as an anti-inflammatory agent.
The present invention provides methods and compositions in which boron compounds/complexes having a central tetrahedral boron atom, covalently bound to four ligands (of either identical or different nature), are utilized to provide anti-inflammatory effects.
Specifically included among the contemplated anti-inflammatory effects are reduction of inflammation of knees, fingers and other joints, reduction of inflammation from insect bites and other localized traumas to the skin, is reduction of scar tissue and improved wound healing. One particularly useful indication for topical treatment is sunburned or otherwise burned skin.
In one aspect of preferred embodiments at least one of the ligands is contemplated to include an oxygen, nitrogen, carbon or sulfur atom, and in more preferred embodiments all four ligands are contemplated to include an oxygen, nitrogen, carbon or sulfur atom.
In another aspect of preferred embodiments, boron is complexed with a saccharide or an amino acid having at least two hydroxyl groups, or one amino- and one hydroxyl group in 1,2- or 1,3-position to each other. Such a spatial arrangement allows formation of stable five- or six-membered rings consisting of one boron atom, two hetero-atoms and 2 or 3 carbon atoms. Such complexes may advantageously comprise fructose, sorbitol, mannitol, xylitol, sorbose, serine or threonine. In its complexes boron is bound more or less tightly to hetero-atoms.
Quantitatively speaking, the stability of boron complexes is contemplated to be proportional to their association constants, and in yet another aspect of the invention, preferred complexes have association constants of at least 50, and more preferred complexes have an association constant between 3,000 and 20,000.
In yet another aspect of this invention, acidic boron complexes may be further converted to salts having sodium, potassium, magnesium or calcium as a counter ion (cation). However, one can successfully used other non-toxic and non-irritating cations such as ammonium, protonated amines, or quaternary ammonium cations.
In yet another aspect of this invention, an active boron compound/complex is included in a suitable cosmetic formulation wherein the compound/complex is provided in a suitable solvent system, a microemulsion form, or a suitable liposome form. These formulations may advantageously contain other ingredients that are also non-toxic and non-irritating to the skin. The composition is also preferably adapted for efficient penetration through the skin stratum corneum barrier when applied topically.